This invention relates to a novel analgesic peptide and a process for the preparation thereof.
Studies of the analgesic mechanism of morphine have suggested that there might be so-called endogenous morphine-like substances which control sensations including algesia and mental operations in vivo. In fact, the presence of a series of opioid peptides such as enkephalin or endorphin has been identified in the brain. There are two types of pentapeptide enkephalins, namely methionine enkephalin and leucine enkephalin, having different physiological effects from one another. Furthermore, endorphin has been known to have analogs such as .alpha., .beta., .gamma., .delta., etc. Among them, .beta.-endorphin consisting of 31 amino acids seems to exhibit the highest analgesic effect. The following literature references give summaries of knowledge heretofore acquired about endorphin:
A. Beaumont, J. Hughes: Ann. Rev. Pharmacol. Toxicol., 19, 245 (1979); T. Oyama: Diagnosis and Treatment, 68, 825 (1980); and Protein, Nucleic acid and Enzyme, 26, No. 2 (1981); Special Number featuring Articles on Opioid Peptides. PA1 Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asp-Gln. PA1 S. Tachibana et al. Nature, 295, 339 (1982); Japanese Patent Application No. 112950/1981, now Japanese Patent Publication (Unexamined) No. 15946/83, corresponding to U.S. Pat. No. 4 481 138; and J. P. Huidobro-Toro et al., Eur. J. Pharmacol., 72. 265 (1981). PA1 N-Me-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-D.Ile-Arg-Pro-Lys-D.Leu-Lys-Trp-NH.sub.2 PA1 Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp. PA1 N-Me-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-D.Ile-Arg-Pro-Lys-D.Leu-Lys-Trp-NH.sub.2 PA1 (A) Assay with guinea pig longitudinal muscle of ileum PA1 H. W. Kosterlitz, A. A. Waterfield: Annu. Rev. Pharmacol., 15, 29 (1975). PA1 (B) Assay with mouse vas deferens PA1 Hughes H. W., Kosterlitz H. W., Leslie F. M.: Br. J. Pharmacol., 53, 371 (1975). PA1 (A) Acetic acid writhing assay PA1 (B) Tail pinch assay PA1 (1)T. J. Haley and W. G. McCormick: Brit. J. Pharmacol., 12, 12 (1957), PA1 (2)F. Haffner: Deut. Med. Wochschr., 55, 731 (1929), PA1 (3)H. Takagi et al.: Jap. Pharmacol., 16, 287 (1966), PA1 (4)J. T. Jr. Litchfield and F. Wilcoxon: J. Pharmacol. Exp. Ther., 96, 99 (1949).
Recent studies have suggested that the endogenous morphine-like substances might occur not only in the brain but also in other regions in vivo. A few peptides regarded as precursors of enkephalin were actually isolated from adrenal medulla. It has also been suggested that some morphine-like substances might occur in the intestinal tract by using immunological methods such as fluorescent antibody method or radioimmuno-assay, or bioassay in vitro. Under these circumstances, some of the present inventors inadvertently found a substance having a morphine-like activity during the purification of a bathoactive intestinal peptide obtained from pig duodenum. Further purification and analysis of the corresponding substance showed that it was a novel peptide having the following primary structure which exhibited a morphine-like activity several hundred times as high as morphine:
Consequently the obtained novel peptide was an opioid peptide, which proved the presence of opioid peptides in the intestinal tract. Further investigations of pharmacological effects of this peptide which had been synthesized separately showed that it exhibited a high analgesic effect when administered intraventricularly and combined selectively with a kappa-receptor belonging to a subclass of an opiate receptor. That is to say, said peptide exhibits an analgesic effect by combining with a receptor different from the .mu.-receptor which combines with morphine, which suggests that it may be an analgesic with no addiction. The following literature references give information about said peptide:
Peptide will rapidly decompose in vivo in general, and undecomposed residue thereof can hardly pass through the blood-brain barrier. Therefore, when an opioid peptide is administered directly to a peripheral region (e.g. intravenously), the resulting analgesic effect is derived from a very small part of the dose. Consequently it must be very effective for improving the usefulness of an opioid peptide, if possible, to formulate it to minimize the decomposition in vivo. This is true also in the case of the above-mentioned, peptide found by some of the present inventors.